The role of statins in the treatment of lung cancer with epidermal growth factor receptor-tyrosine kinase inhibitors: a protocol for systematic review and meta-analysis.

Introduction: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have substantially improved outcomes in patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, both primary and acquired resistance limit their long-term efficacy. Statins have shown potential to modulate cholesterol metabolism and EGFR-related signaling, and may therefore influence treatment outcomes in this population. Current clinical evidence remains inconsistent and heterogeneous. This study aims to systematically evaluate whether statin use is associated with improved efficacy outcomes in patients with EGFR-mutant NSCLC receiving EGFR-TKIs, while also assessing reported adverse events as a supplementary safety outcome. Methods: This review will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. PubMed, EMBASE, Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Data, and the Chinese Biomedical Literature Database will be searched for randomized controlled trials and observational studies evaluating statin exposure in patients with EGFR-mutant NSCLC receiving EGFR-TKIs. The websites of key academic societies and clinical trial registries will also be reviewed. Two reviewers will independently select studies and extract data. Risk of bias will be assessed using the Cochrane Risk-of-Bias tool 2.0 and Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I), with particular attention to confounding and time-related biases in observational studies. Overall survival will be the primary outcome, and progression-free survival will be the key secondary outcome. Randomized and observational studies will be synthesized separately, and subgroup, sensitivity, and reporting bias analyses will be conducted where appropriate. Discussion: Preclinical studies suggest that statins may enhance the antitumor activity of EGFR-TKIs, but the clinical evidence remains inconsistent. This protocol will synthesize available evidence to evaluate whether statin exposure is associated with the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and to explore potential sources of heterogeneity across studies. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251111062, PROSPERO CRD420251111062.